J Breast Cancer.  2013 Sep;16(3):266-273. 10.4048/jbc.2013.16.3.266.

Association of Human Epidermal Growth Factor Receptor 2 with Radiotherapy Resistance in Patients with T1N0M0 Breast Cancer

• Kim HA
• Kim EK
• Kim MS
• Yu JH
• Lee MR
• Lee HK
• Suh YJ
• Noh WC
• Korean Breast Cancer Society

• KMID: 2286377
• DOI: http://doi.org/10.4048/jbc.2013.16.3.266

Abstract

PURPOSE
Preclinical studies have shown that human epidermal growth factor receptor 2 (HER2) status is associated with resistance to radiotherapy (RT). In this study, we evaluated the overall survival of a T1N0M0 breast cancer cohort in Korea according to the use of RT and the HER2 status.
METHODS
We analyzed data collected from 11,552 patients with invasive breast cancer who were enrolled in the Korean Breast Cancer Society Registration Program between 1999 and 2007. Data on the TNM stage, estrogen receptor status, progesterone receptor status, HER2 status, operation method, and the use of RT were analyzed.
RESULTS
The median follow-up period was 51 months. A significant improvement in overall survival after RT was observed only in the HER2(-) group. In this group, the 10-year overall survival rate was 95.5% for patients who did not receive RT and 96.3% for patients who received RT (p=0.037). In contrast, in the HER2(+) group, RT was not associated with a survival benefit (p=0.887). Multivariate analysis showed that RT was significantly associated with a reduction in mortality in the HER2(-) group (hazard ratio, 0.738; 95% confidence interval, 0.549-0.993; p=0.045).
CONCLUSION
We found that postoperative RT was not associated with a survival benefit in HER2(+) breast cancer patients, suggesting that HER2(+) breast cancers could be RT resistant.

Keyword

Breast neoplasms; Human epidermal growth factor receptor 2; Radiotherapy; Survival

MeSH Terms

Breast
Breast Neoplasms
Cohort Studies
Epidermal Growth Factor
Estrogens
Follow-Up Studies
Humans
Korea
Multivariate Analysis
Receptor, Epidermal Growth Factor
Receptor, erbB-2
Receptors, Progesterone
Survival Rate
Epidermal Growth Factor
Estrogens
Receptor, Epidermal Growth Factor
Receptor, erbB-2
Receptors, Progesterone

Figure

• 

  Figure 1 Patient selection flow chart. ER=estrogen receptor; PR=progesterone receptor; HER2=human epidermal growth factor receptor 2.

• 

  Figure 2 (A) Overall survival for all patients. (B) Overall survival according to human epidermal growth factor receptor 2 (HER2) status. (C) Overall survival according to operation methods. (D) Overall survival according to whether radiotherapy (RT) or not. BCS=breast-conserving surgery.

• 

  Figure 3 Effect of radiotherapy (RT) on breast cancer mortality after curative operation (A) in the human epidermal growth receptor 2 (HER2) (-) group and (B) in the HER2(+) group.

Reference

1. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999; 353:1641–1648.

2. Danish Breast Cancer Cooperative Group. Nielsen HM, Overgaard M, Grau C, Jensen AR, Overgaard J. Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c randomized studies. J Clin Oncol. 2006; 24:2268–2275.

3. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997; 337:949–955.

4. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011; 378:1707–1716.

5. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst. 2005; 97:116–126.

6. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 366:2087–2106.

7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235:177–182.

8. Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004; 5:63–69.

9. Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010; 28:1684–1691.

10. Millar EK, Graham PH, O'Toole SA, McNeil CM, Browne L, Morey AL, et al. Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol. 2009; 27:4701–4708.

11. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008; 26:2373–2378.

12. Pietras RJ, Poen JC, Gallardo D, Wongvipat PN, Lee HJ, Slamon DJ. Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 1999; 59:1347–1355.

13. No M, Choi EJ, Kim IA. Targeting HER2 signaling pathway for radiosensitization: alternative strategy for therapeutic resistance. Cancer Biol Ther. 2009; 8:2351–2361.

14. Pirollo KF, Tong YA, Villegas Z, Chen Y, Chang EH. Oncogene-transformed NIH 3T3 cells display radiation resistance levels indicative of a signal transduction pathway leading to the radiation-resistant phenotype. Radiat Res. 1993; 135:234–243.

15. Kyndi M, Sørensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2008; 26:1419–1426.

16. Ahn SH, Son BH, Kim SW, Kim SI, Jeong J, Ko SS, et al. Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea: a report from the Korean Breast Cancer Society. J Clin Oncol. 2007; 25:2360–2368.

17. Lee JA, Kim KI, Bae JW, Jung YH, An H, Lee ES, et al. Triple negative breast cancer in Korea-distinct biology with different impact of prognostic factors on survival. Breast Cancer Res Treat. 2010; 123:177–187.

18. The Korean Breast Cancer Society. Survival analysis of Korean breast cancer patients diagnosed between 1993 and 2002 in Korea: a nationwide study of the cancer registry. J Breast Cancer. 2006; 9:214–229.

19. Han W, Kang SY. Korean Breast Cancer Society. Relationship between age at diagnosis and outcome of premenopausal breast cancer: age less than 35 years is a reasonable cut-off for defining young age-onset breast cancer. Breast Cancer Res Treat. 2010; 119:193–200.

20. Jung KW, Park S, Kong HJ, Won YJ, Lee JY, Seo HG, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. Cancer Res Treat. 2012; 44:11–24.

21. Rozan S, Vincent-Salomon A, Zafrani B, Validire P, De Cremoux P, Bernoux A, et al. No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int J Cancer. 1998; 79:27–33.

22. Albert JM, Gonzalez-Angulo AM, Guray M, Sahin A, Strom EA, Tereffe W, et al. Estrogen/progesterone receptor negativity and HER2 positivity predict locoregional recurrence in patients with T1a,bN0 breast cancer. Int J Radiat Oncol Biol Phys. 2010; 77:1296–1302.

23. Wang Y, Yin Q, Yu Q, Zhang J, Liu Z, Wang S, et al. A retrospective study of breast cancer subtypes: the risk of relapse and the relations with treatments. Breast Cancer Res Treat. 2011; 130:489–498.

24. Buchholz TA. Radiotherapy and survival in breast cancer. Lancet. 2011; 378:1680–1682.

25. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002; 347:1227–1232.

26. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002; 347:1233–1241.

27. Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z. Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther. 2003; 2:1113–1120.

28. Sambade MJ, Kimple RJ, Camp JT, Peters E, Livasy CA, Sartor CI, et al. Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts. Int J Radiat Oncol Biol Phys. 2010; 77:575–581.

29. Horton JK, Halle J, Ferraro M, Carey L, Moore DT, Ollila D, et al. Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial. Int J Radiat Oncol Biol Phys. 2010; 76:998–1004.

30. Caussa L, Kirova YM, Gault N, Pierga JY, Savignoni A, Campana F, et al. The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study. Eur J Cancer. 2011; 47:65–73.